Emerging therapeutic landscape: Incretin agonists in chronic kidney disease management.

The increasing incidence of chronic kidney disease (CKD) poses a significant public health concern, prompting heightened attention to its treatment. Incretins, including glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide, are intestinal peptides released after nutrient intake, known for their hypoglycemic effects in diabetes management. Recent advancements highlight the promising outcomes of GLP-1 receptor agonists in reducing CKD risk factors and improving renal outcomes. The multifaceted functions of GLP-1, such as its anti-obesity, anti-hypertensive, anti-hyperglycemic, anti-lipid, anti-inflammatory, and endothelial function protective properties, contribute to its potential as a therapeutic agent for CKD. Although experiments suggest the potential benefits of incretin in CKD, a comprehensive understanding of its specific mechanisms is still lacking. This review aims to provide a detailed examination of current evidence and potential future directions, emphasizing the promising yet evolving landscape of incretin agonists in the context of CKD.

Epidemiology of 369 diseases and injuries attributable to 84 risk factors: 1990-2019 with 2040 projection.

The global burden of diseases and injuries poses complex and pressing challenges. This study analyzed 369 diseases and injuries attributed to 84 risk factors globally from 1990 to 2019, projecting trends to 2040. In 2019, global risks caused 35 million deaths. Non-communicable diseases were responsible for 8.2 million deaths, primarily from air pollution (5.5 million). Cardiovascular disease from air pollution had a high age-standardized disability-adjusted life year rate (1,073.40). Communicable, maternal, neonatal, and nutritional diseases caused 1.4 million deaths, mainly due to unsafe water and sanitation. Occupational risks resulted in 184,269 transport-related deaths. Behavioral risks caused 21.6 million deaths, with dietary factors causing 6.9 million cardiovascular deaths. Diabetes linked to sugar-sweetened beverages showed significant growth (1990-2019). Metabolic risks led to 18.6 million deaths. Projections to 2040 indicated persistent challenges, emphasizing the urgent need for targeted interventions and policies to alleviate the global burden of diseases and injuries.

Exploring the multi-targeting phytoestrogen potential of Calycosin for cancer treatment: A review.

Cancer remains a significant challenge in the field of oncology, with the search for novel and effective treatments ongoing. Calycosin (CA), a phytoestrogen derived from traditional Chinese medicine, has garnered attention as a promising candidate. With its high targeting and low toxicity profile, CA has demonstrated medicinal potential across various diseases, including cancers, inflammation, and cardiovascular disease. Studies have revealed that CA possesses inhibitory effects against a diverse array of cancers. The underlying mechanism of action involves a reduction in tumor cell proliferation, induction of tumor cell apoptosis, and suppression of tumor cell migration and invasion. Furthermore, CA has been shown to enhance the efficacy of certain chemotherapeutic drugs, making it a potential component in treating malignant tumors. Given its high efficacy, low toxicity, and multi-targeting characteristics, CA holds considerable promise as a therapeutic agent for cancer treatment. The objective of this review is to present a synthesis of the current understanding of the antitumor mechanism of CA and its research progress.

20(S)-Ginsenoside Rh2 inhibits hepatocellular carcinoma by suppressing angiogenesis and the GPC3-mediated Wnt/ß­catenin signaling pathway.

20(S)-Ginsenoside Rh2 has significant anti-tumor effects in various types of cancers, including human hepatocellular carcinoma (HCC). However, its molecular targets and mechanisms of action remain largely unknown. Here, we aim to elucidate the potential mechanisms by which Rh2 suppresses HCC growth. We first demonstrate the role of Rh2 in inhibiting angiogenesis. We observe that Rh2 effectively suppresses cell proliferation and induces apoptosis in HUVECs. Furthermore, Rh2 significantly inhibits HepG2-stimulated HUVEC proliferation, migration and tube formation, accompanied by the downregulation of VEGF and MMP-2 expressions. We also reveal that Rh2 inhibits HCC growth through the downregulation of glypican-3-mediated activation of the Wnt/ß-catenin pathway. We observe a dose-dependent inhibition of proliferation and induction of apoptosis in HepG2 cells upon Rh2 treatment, which is mediated by the inhibition of glypican-3/Wnt/ß-catenin signaling. Moreover, downregulation of glypican-3 expression enhances the effects of Rh2 on the glypican-3/Wnt/ß-catenin signaling pathway, resulting in greater suppression of tumor growth in HepG2 cells. Collectively, our findings shed light on the molecular mechanisms through which Rh2 modulates HCC growth, which involve the regulation of angiogenesis and the glypican-3/Wnt/ß-catenin pathway. These insights may pave the way for the development of novel therapeutic strategies targeting these pathways for the treatment of HCC.

The impact of the senescent microenvironment on tumorigenesis: Insights for cancer therapy.

The growing global burden of cancer, especially among people aged 60 years and over, has become a key public health issue. This trend suggests the need for a deeper understanding of the various cancer types in order to develop universally effective treatments. A prospective area of research involves elucidating the interplay between the senescent microenvironment and tumor genesis. Currently, most oncology research focuses on adulthood and tends to ignore the potential role of senescent individuals on tumor progression. Senescent cells produce a senescence-associated secretory phenotype (SASP) that has a dual role in the tumor microenvironment (TME). While SASP components can remodel the TME and thus hinder tumor cell proliferation, they can also promote tumorigenesis and progression via pro-inflammatory and pro-proliferative mechanisms. To address this gap, our review seeks to investigate the influence of senescent microenvironment changes on tumor development and their potential implications for cancer therapies.

Unraveling the role of the FHL family in cardiac diseases: Mechanisms, implications, and future directions.

Heart diseases are a major cause of morbidity and mortality worldwide. Understanding the molecular mechanisms underlying these diseases is essential for the development of effective diagnostic and therapeutic strategies. The FHL family consists of five members: FHL1, FHL2, FHL3, FHL4, and FHL5/Act. These members exhibit different expression patterns in various tissues including the heart. FHL family proteins are implicated in cardiac remodeling, regulation of metabolic enzymes, and cardiac biomechanical stress perception. A large number of studies have explored the link between FHL family proteins and cardiac disease, skeletal muscle disease, and ovarian metabolism, but a comprehensive and in-depth understanding of the specific molecular mechanisms targeting FHL on cardiac disease is lacking. The aim of this review is to explore the structure and function of FHL family members, to comprehensively elucidate the mechanisms by which they regulate the heart, and to explore in depth the changes in FHL family members observed in different cardiac disorders, as well as the effects of mutations in FHL proteins on heart health.

Changing trends of the diseases burden attributable to high BMI in Asia from 1990 to 2019: results from the global burden of disease study 2019.

OBJECTIVE: To analyse the trends of diseases burden attributed to high body mass index (BMI), including overweight and obesity, in Asia from 1990 to 2019. DESIGN: Observational study. SETTING: The data of 45 countries and regions in Asia were obtained from the Global Burden of Disease Study 2019 database. MAIN OUTCOME MEASURES: Numbers, age-standardised rate (ASR) of deaths and disability-adjusted life years (DALYs), and the corresponding estimated annual percentage changes (EAPCs), attributable to high BMI in Asia from 1990 to 2019, were analysed by regions, genders and age. We also analysed changes in the causes of deaths and DALYs that are attributable to high BMI over this period. RESULTS: In 2019, all causes deaths attributable to high BMI in Asia were 2 329 503, with increases by 265% compared with 1990. Over three decades, DALYs related to high BMI have increased by 268%. The ASRs of deaths and DALYs in Asia both showed continuous upward trends during this period (EAPC 1.39; 95% certainty interval [95% CI] 1.35 to 1.43 for deaths; EAPC 1.8; 95% CI 1.76 to 1.84 for DALYs), while both were declined in high-income areas (EAPC -2.03 and -1.26). By geographical regions, disease burden in Central Asia and West Asia have been fluctuating at high levels, but high-income Asia Pacific showed decreasing trends of ASR of deaths (EAPC -2.03) and DALYs (EAPC -1.26). Over this period, disease burden in Asia was changing from women to men, and tends to ageing. In addition, diabetes were the diseases most affected by high BMI, and cancer burden was high in middle-aged and elderly people. CONCLUSIONS: The disease burden attributed to high BMI in Asia has experienced great changes. It is necessary to promote the prevention of obesity and chronic diseases in a comprehensive manner, especially in low-income areas, men and elderly.

Global, Regional, and National Epidemiology of Diabetes in Children From 1990 to 2019.

Importance: Diabetes in children is a global epidemic that causes various medical conditions associated with an increased incidence of premature death. Objective: To investigate the trends in diabetes incidence, mortality, and disability-adjusted life-years (DALYs) in children, with risk factors for diabetes-associated death, from 1990 to 2019. Design, Setting, and Participants: This was a cross-sectional study that used data from the Global Burden of Diseases (GBD) 2019 in 204 countries and territories. Children with diabetes who were aged 0 to 14 years were included in the analysis. Data were analyzed from December 28, 2022, to January 10, 2023. Exposure: Childhood diabetes from 1990 to 2019. Main Outcome Measures: Incidence, all-cause and cause-specific deaths, DALYs, and corresponding estimated annual percentage changes (EAPCs). These trends were stratified according to region, country, age, sex, and Sociodemographic Index (SDI). Results: A total of 1 449 897 children (738 923 male [50.96%]) were included in the analysis. In 2019, there were 227 580 incident cases of childhood diabetes worldwide. Cases of childhood diabetes increased by 39.37% (95% uncertainty interval [UI], 30.99%-45.45%) from 1990 to 2019. Over 3 decades, diabetes-associated deaths decreased from 6719 (95% UI, 4823-8074) to 5390 (95% UI, 4450-6507). The global incidence rate increased from 9.31 (95% UI, 6.56-12.57) to 11.61 (95% UI, 7.98-15.98) per 100 000 population; however, the diabetes-associated death rate decreased from 0.38 (95% UI, 0.27-0.46) to 0.28 (95% UI, 0.23-0.33) per 100 000 population. Among the 5 SDI regions, the low SDI region had the highest childhood diabetes-associated mortality rate in 2019. Regionally, North Africa and the Middle East had the largest increase in incidence (EAPC, 2.06; 95% CI, 1.94-2.17). Among 204 countries, Finland had the highest national incidence of childhood diabetes in 2019 (31.60 per 100 000 population; 95% UI, 22.65-40.36), Bangladesh had the highest diabetes-associated mortality rate (1.16 per 100 000 population; 95% UI, 0.51-1.70), and the United Republic of Tanzania had the highest DALYs rate (100.16 per 100 000 population; 95% UI, 63.01-155.88). Globally, environmental/occupational risk, nonoptimal temperature, high temperature, and low temperature were key risk factors for childhood diabetes-associated mortality in 2019. Conclusions and Relevance: Childhood diabetes is an increasing global health challenge with rising incidence. Results of this cross-sectional study suggest that despite the global decline in deaths and DALYs, the number of deaths and DALYs remains high among children with diabetes, especially in low SDI regions. Improved understanding of the epidemiology of diabetes in children may facilitate prevention and control.

Optimizing glycation control in diabetes: An integrated approach for inhibiting nonenzymatic glycation reactions of biological macromolecules.

Diabetes is a multifactorial disorder that increases mortality and disability due to its complications. A key driver of these complications is nonenzymatic glycation, which generates advanced glycation end-products (AGEs) that impair tissue function. Therefore, effective nonenzymatic glycation prevention and control strategies are urgently needed. This review comprehensively describes the molecular mechanisms and pathological consequences of nonenzymatic glycation in diabetes and outlines various anti-glycation strategies, such as lowering plasma glucose, interfering with the glycation reaction, and degrading early and late glycation products. Diet, exercise, and hypoglycemic medications can reduce the onset of high glucose at the source. Glucose or amino acid analogs such as flavonoids, lysine and aminoguanidine competitively bind to proteins or glucose to block the initial nonenzymatic glycation reaction. In addition, deglycation enzymes such as amadoriase, fructosamine-3-kinase, parkinson's disease protein, glutamine amidotransferase-like class 1 domain-containing 3A and terminal FraB deglycase can eliminate existing nonenzymatic glycation products. These strategies involve nutritional, pharmacological, and enzymatic interventions that target different stages of nonenzymatic glycation. This review also emphasizes the therapeutic potential of anti-glycation drugs for preventing and treating diabetes complications.

Identification of Potential Indicators for Survival in Patients with Thyroid Cancer Based on Expression of FAM3 Members.

Thyroid cancer (THCA) is a common head and neck malignancy. The family with sequence similarity 3 (FAM3) is a cytokine-like gene family with four members, which is presumed to participate in the development of many cancer types. However, the expression patterns of FAM3s in THCA and their prognostic values, have not yet been established. We investigated differential expressions of FAM3 mRNA and protein in THCA, then validated the findings for FAM3B by immunohistochemistry. We also investigated survival data with respect to FAM3 expression patterns in patients with THCA. FAM3s information regarding their relationships with clinical pathological parameters were obtained and FAM3 mutations were assessed. KEGG and GO pathway regarding FAM3C were obtained using online databases. To investigate potential correlations between FAM3s and immune cell infiltration, we investigated the roles of FAM3s in immune cells of patients with THCA. The mRNA expression of FAM3C were significantly elevated in THCA tissues; high expression levels of FAM3C protein were also observed in THCA tissues. A significant association between the pathological stage and the expression of FAM3C was found in patients with THCA. Patients with THCA who had high mRNA expression levels of FAM3C exhibited significantly more favorable prognosis, compared with patients who had low mRNA expression levels of FAM3C. Overall, FAM3C may play vital roles in the pathogenesis and development of THCA, and these findings constitute novel insights for biomarkers of immunotherapeutic targeted agents and may aid in the identification of prognostic biomarkers for THCA.

Role of dysfunctional peri-organ adipose tissue in metabolic disease.

Metabolic disease is a complex disorder defined by a group with interrelated factors. There is growing evidence that obesity can lead to a variety of metabolic diseases, including diabetes and cardiovascular disease. Excessive adipose tissue (AT) deposition and ectopic accumulation can lead to increased peri-organ AT thickness. Dysregulation of peri-organ (perivascular, perirenal, and epicardial) AT is strongly associated with metabolic disease and its complications. The mechanisms include secretion of cytokines, activation of immunocytes, infiltration of inflammatory cells, involvement of stromal cells, and abnormal miRNA expression. This review discusses the associations and mechanisms by which various types of peri-organ AT affect metabolic diseases while addressing it as a potential future treatment strategy.

Advances in understanding the role and mechanisms of tumor stem cells in HER2-positive breast cancer treatment resistance (Review).

Approximately 15-20% of breast carcinomas exhibit human epidermal growth factor receptor (HER2) protein overexpression. HER2-positive breast cancer (BC) is a heterogeneous and aggressive subtype with poor prognosis and high relapse risk. Although several anti-HER2 drugs have achieved substantial efficacy, certain patients with HER2-positive BC relapse due to drug resistance after a treatment period. There is increasing evidence that BC stem cells (BCSCs) drive therapeutic resistance and a high rate of BC recurrence. BCSCs may regulate cellular self-renewal and differentiation, as well as invasive metastasis and treatment resistance. Efforts to target BCSCs may yield new methods to improve patient outcomes. In the present review, the roles of BCSCs in the occurrence, development and management of BC treatment resistance were summarized; BCSC-targeted strategies for the treatment of HER2-positive BC were also discussed.

Secular trends of epidemiologic patterns of chronic kidney disease over three decades: an updated analysis of the Global Burden of Disease Study 2019.

OBJECTIVES: To assess the characteristics of the global death burden imposed by chronic kidney disease (CKD) and the attributable risk factors from 1990 to 2019 to help inform a framework for policy discussions, resource allocation and research priorities. DESIGN: A population-based observational study. SETTING: The death data and relative risk factors were obtained from the Global Burden of Disease (GBD) Study 2019 database. MAIN OUTCOME MEASURES: Based on the GBD database, we estimated the death burden attributable to CKD stratified by sociodemographic index (SDI), geographic location, sex, age group, time period and risk factors from 1990 to 2019. RESULTS: Over three decade study period, the global number of CKD-related deaths increased from 0.60 million (95% uncertainty interval (UI): 0.57-0.63 million) in 1990 to 1.43 million (95% UI: 1.31-1.52 million) in 2019. The age-standardised death rate (ASDR) of CKD, among all causes, increased from 15th in 1990 to 10th in 2019. Globally, the ASDR in males was higher than that in females. CKD-related deaths mainly occurred in those aged over 50 years, especially in regions with higher SDIs. The ASDR was negatively related to SDI (ρ=-0.603, p<0.0001). Among risk factors, metabolic risk factors, especially systolic blood pressure, fasting plasma glucose and body mass index, were the main contributors to CKD-related deaths. Although the high-temperature-related death burden was low, the trend increased sharply in lower SDI regions. CONCLUSIONS: CKD-related deaths continue to increase, with the majority occurring in elderly adults. The CKD-related death burden is higher in males than in females. Additionally, the increasing high-temperature-related death burdens in lower SDI regions should receive social attention.

Integrated multi-omics analyses reveal effects of empagliflozin on intestinal homeostasis in high-fat-diet mice.

Obesity has become a global epidemic, associated with several chronic complications. The intestinal microbiome is a critical regulator of metabolic homeostasis and obesity. Empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has putative anti-obesity effects. In this study, we used multi-omics analysis to determine whether empagliflozin regulates metabolism in an obese host through the intestinal microbiota. Compared with obese mice, the empagliflozin-treated mice had a higher species diversity of gut microbiota, characterized by a reduction in the Firmicutes/Bacteroides ratio. Metabolomic analysis unambiguously identified 1,065 small molecules with empagliflozin affecting metabolites mainly enriched in amino acid metabolism, such as tryptophan metabolism. RNA sequencing results showed that immunoglobulin A and peroxisome proliferator-activated receptor signaling pathways in the intestinal immune network were activated after empagliflozin treatment. This integrative analysis highlighted that empagliflozin maintains intestinal homeostasis by modulating gut microbiota diversity and tryptophan metabolism. This will inform the development of therapies for obesity based on host-microbe interactions.

Global burden of non-alcoholic fatty liver disease in 204 countries and territories from 1990 to 2019.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a growing epidemic linked to metabolic disease and is the most prevalent cause of chronic liver disease. We, therefore, designed the study to analyze the global and regional burden of NAFLD from 1990 to 2019. METHODS: We collected data on NAFLD from the Global Burden of Disease study 2019, aiming to conduct a systematic assessment of the changes and trends in NAFLD in 204 countries. Secondary analysis of NAFLD was conducted using age-standardized rates (ASRs) and estimated annual percentage changes (EAPCs) to show the changing trends and development characteristics. Data statistics and visualization were executed with the R program. RESULTS: Globally, incidence, deaths and disability-adjusted life years (DALYs) of NAFLD all showed an upward trend. Between 1990 and 2019, the incidence of NAFLD increased by 95.4%, from 88,177 to 172,330 cases. Meanwhile, the ASIR of the middle SDI region had the highest increase, followed by the low-middle SDI region. Of all countries, the most incident cases were in China, which accounted for approximately 23.6% of NAFLD. China was also the country with the largest cases of deaths and DALYs. And behavioral risk, metabolic factors, smoking and high fasting plasma glucose were the critical risk factors associated with the mortality and DALYs of NAFLD. CONCLUSION: NAFLD has become a considerable health burden in many countries. Therefore, we should control the risk factors of NAFLD and take corresponding measures to achieve its early prevention and treatment.

The protective effects of SGLT-2 inhibitors, GLP-1 receptor agonists, and RAAS blockers against renal injury in patients with type 2 diabetes.

Diabetic kidney disease is one of the most severe complications of type 2 diabetes mellitus. Patients with diabetic kidney disease have a worse prognosis in terms of mortality and morbidity, compared with patients who have diabetes alone. Strict control of blood pressure and blood glucose is the primary method for prevention of initial kidney damage and delaying further progression of existing damage. Other management approaches include the use of exogenous drugs that can effectively protect the kidneys from diabetes, such as sodium-glucose transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and renin-angiotensin-aldosterone system blockers. These drugs may protect against kidney injury through various molecular mechanisms. This review focuses on renal impairment in patients with type 2 diabetes; it discusses the direct and indirect effects of sodium-glucose transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and renin-angiotensin-aldosterone system blockers on diabetic kidney disease. Finally, it discusses the effects of combination treatment with two or three types of drugs in patients with chronic kidney disease.

Irisin protects against obesity-related chronic kidney disease by regulating perirenal adipose tissue function in obese mice.

BACKGROUND: Compared with typical visceral fat deposits in obesity and metabolic syndrome, perirenal adipose tissue (PRAT) dysfunction is more closely linked to obesity-related chronic kidney disease (OB-CKD). The myokine irisin reportedly promotes positive outcomes in metabolic disease. This study investigated whether irisin could reduce urinary albumin excretion and demonstrate renoprotective effects through the regulation of PRAT function in obese mice. METHODS: C57BL/6 J mice received a high-fat diet (HFD) with or without concurrent administration of irisin. Glucose tolerance, plasma levels of free fatty acids, and urinary albumin excretion were assessed, along with renal morphology. The vascular endothelial growth factor and nitric oxide in glomeruli were also analyzed, in addition to PRAT function-associated proteins. RESULTS: Irisin administration significantly reduced the final body weight, fat mass, and free fatty acids, without reducing PRAT mass, in HFD mice. Furthermore, irisin decreased urinary albumin excretion and attenuated both renal fibrosis and lipid accumulation. Irisin administration led to increases in PRAT function-associated proteins, including sirtuin1, uncoupling protein-1, and heme-oxygenase-1. Ex vivo treatment of PRAT and glomeruli with irisin also restored PRAT function. Finally, irisin treatment restored the vascular endothelial growth factor-nitric oxide axis. CONCLUSIONS: Irisin attenuated metabolic disorders and protected against OB-CKD by normalizing the PRAT-kidney axis. These results suggest that agents targeting PRAT activation might be useful for treatment of OB-CKD.

Glutaminolysis and CD4+ T-cell metabolism in autoimmunity: From pathogenesis to therapy prospects.

The recent increase in the pathogenesis of autoimmune diseases revealed the critical role of T cells. Investigation into immunometabolism has drawn attention to metabolic processes other than glycometabolism. In rapidly dividing immune cells, including T lymphocytes, the consumption of glutamine is similar to or higher than that of glucose even though glucose is abundant. In addition to contributing to many processes critical for cellular integrity and function, glutamine, as the most abundant amino acid, was recently regarded as an immunomodulatory nutrient. A better understanding of the biological regulation of glutaminolysis in T cells will provide a new perspective for the treatment of autoimmune diseases. In this review, we summarized the current knowledge of glutamine catabolism in CD4+ T-cell subsets of autoimmunity. We also focused on potential treatments targeting glutaminolysis in patients with autoimmune diseases. Knowledge of immunometabolism is constantly evolving, and glutamine metabolism may be a potential therapeutic target for autoimmune disease therapy.

Global Burden of cardiomyopathy and myocarditis in the older adults from 1990 to 2019.

Background: Cardiomyopathy and myocarditis (CM-MC) are common chronic diseases causing heart failure in older adults. We aimed to analyze the burden of CM-MC in older adults aged 60-89 years at the global, regional, and national levels in 204 countries from 1990 to 2019. Methods: Detailed data on CM-MC from 1990 to 2019 were analyzed from the Global Burden of Diseases Study 2019, including incidence, mortality, disability-adjusted life years (DALYs) and the proportion of deaths caused by different risks factors. All results are presented as numbers, age-standardized rates per 100,000 person-years and estimated annual percentage change (EAPC) with an uncertainty interval of 95%. Results: Globally, there were 475,458 (339,942-638,363) incidence cases from CM-MC in 2019; with an age-standardized incidence rate (ASIR) of 16 (13-19.3) per 100,000 person-years. And there were 185,308 (154,610-200,448) deaths, with the age-standardized mortality rate (ASMR) being 4.4 (3.7-4.8). CM-MC resulted in 3,372,716 (2,931,247-3,693,622) DALYs, with an age-standardized DALYs rate (ASDR) of 114.8 (98.7-126.1). Estimated annual percentage change (EAPCs) for ARIS, ARMS, and ARDS has decreased. At the national level, the United States of America had the highest mortality [21,372 (18,924-24,241)] and disability-adjusted life years [407,712 (370,234-470,165)]. And China had the highest number of incident cases [122, 266 (85,925-166,095)]. Globally, high systolic blood pressure and alcohol consumption were the top two risk factors for the proportion of CM-MC deaths. Conclusion: CM-MC is still an important cause of early death and chronic disability in older adults. Based on this study, public health agencies should seek more effective methods to prevent and treat CM-MC.